DESCRIPTION: Ebola virus is a newly emerging pathogen which causes a severe hemorrhagic disease with fatality rates of 30 to 90% in humans and non-human primates. Sporadic outbreaks in humans and primates in Africa and in imported primates in the United States over the past ten years highlight the health risk posed by this virus. The overall goal of this proposal is to functionally and immunologically characterize the glycoproteins of Ebola virus and define the host molecules with which these glycoproteins interact. A long term objective of this project is to understand the role the glycoproteins play in pathogenesis and design therapeutic or prophylactic means based on this understanding. To characterize the glycoproteins of this hazardous virus, the PI has developed pseudotypes in which the glycoproteins of Ebola are incorporated into a retroviral particle to allow safe and convenient analysis of both glycoprotein function and host immune response to the glycoproteins. He has used these pseudotypes to ascertain that a large number of cell types from a very wide variety of species are permissive for Ebola glycoprotein (Ebo-GP) mediated entry. Receptor availability is often a major determinant of viral tropism and pathogenesis, therefore the pseudotypes will be useful for analysis of these properties of Ebola. The only cells which were found to be specifically resistant to Ebo-GP mediated entry are lymphoid cells and their specific resistance suggests that these cells lack functional receptors for this virus. He will use lymphoid cells in genetic complementation assays to identify the host receptor for Ebola virus. Comparison of the utilization of this receptor by various strains of Ebola may shed light on pathogenic differences seen with these strains. In addition, the PI has demonstrated that the Ebola glycoprotein in the pseudotyped virus is neutralized by sera specific for Ebo-GP in a manner very similar to Ebola itself. Therefore, he will use the pseudotyped viruses to analyze host immune response to the Ebo-GP. In these studies he proposes to identify epitopes as possible vaccine candidates and also to identify potential therapeutic neutralizing antibodies. Finally, he will use the pseudotypes to analyze the function of the Ebola glycoprotein and will attempt to utilize this basic knowledge for design of potential therapeutics. The specific aims to be conducted during the tenure of this grant are: 1) Identification and characterization of the cellular receptor for Ebola virus, 2) Analysis of the immune response to the Ebola virus glycoproteins, 3) Functional characterization of the Ebola glycoproteins.